Because neurons of the mature central nervous system ("CNS") are highly specialized and in general do not replace themselves, death or degeneration of cells in the nervous system has far more serious consequences than it does in other organs. Abnormal neuronal death can be rapid and widespread as in traumatic brain injury, or can occur over many years among very specific populations of neurons as in chronic neurodegenerative diseases.
Despite this diversity, substantial evidence now points to pernicious overactivity of normal neurotransmitter systems as a contributory mechanism in many instances of pathological neuronal degeneration. In particular, overstimulation of neuronal receptors for L-glutamate, the brain's most prevalent excitatory amino acid ("EAA") neurotransmitter, is now well established as a causal or exacerbating factor in several acute neurological disorders, and has been proposed to underlie a number of chronic neurodegenerative diseases as well [Choi, D. W., Neuron 1:623 (1988); Choi, D. W., Cerebrov. and Brain Metab. Rev. 2:105 (1990); and Albers, G. W. et al. Ann. Neurol. 25:398 (1989)].
In the mammalian brain, glutamate interacts with three major classes or receptors, i.e., N-methyl-D-aspartate ("NMDA") receptors, non-NMDA receptors and metabotropic receptors [Watkins, J. C. et al., Trends Neurosci. 10:265 (1987)]. While triggering distinctive postsynaptic responses, all three classes of glutamate receptors can act to increase the intracellular concentration of free Ca.sup.2+ in nerve cells [MacDermott, A. B. Nature 321:519 (1986)]. Thus, binding of glutamate to the NMDA receptor opens a cation-selective channel that is markedly permeable to Ca.sup.2+, leading to a large and rapid increase in intracellular Ca.sup.2+. Although non-NMDA receptors are in most instances linked to cation channels that largely exclude calcium, they can indirectly promote Ca.sup.2+ entry into neurons by depolarizing the cell membrane, which in turn opens voltage-activated Ca.sup.2+ -channels The so-called "metabotropic receptor" on the other hand, is not associated with an ion channel but can promote the release of Ca.sup.2+ from intracellular stores via the second-messenger inositol triphosphate.
Irrespective of the triggering mechanism, prolonged elevation of cytosolic Ca.sup.2+ is believed to be a key event in the initiation of neuronal destruction. Adverse consequences of elevated intracellular Ca.sup.2+ include derangement of mitochondrial respiration, activation of Ca.sup.2+ -dependent proteases, lipases and endonucleases, free radical formation and lipid peroxidation of the cell membrane.
There are few effective treatments for excitotoxic pathologies. In recent years, much effort has been directed at developing antagonists of glutamate receptors as potential neuroprotective agents. To date, most of this research has focused on devising antagonists of the NMDA receptors and/or their associated ion channels. NMDA receptors are an attractive therapeutic target because they can be antagonized noncompetitively via a number of different pharmacological binding sites as well as competitively at the glutamate recognition site. Concern about possible behavioral and other CNS side effects of NMDA antagonists has led to an emphasis on using these drugs only to treat acute disorders.
Non-NMDA receptors constitute a broad category of postsynaptic receptor sites which, as is the case for NMDA receptors, are directly linked to ion channels. Specifically, the receptor sites are physically part of specific ion channel proteins. Non-NMDA receptors have been broadly characterized into two major subclasses based on selectively for the aforementioned compounds: kainate receptors and AMPA/quisqualate receptors [see Watkins, J. C. et al., Trends Neurosci. 10:265 (1987)]. AMPA is an abbreviation for .alpha.-amino-3-hydroxyl-5-methyl-4-isoazole propionic acid. These two subclasses may overlap substantially in their pharmacology, and in their relationship to neuronal function and pathology. We will thus broadly categorize these subclasses as "non-NMDA" receptors, and present evidence that the compounds claimed block postsynaptic responses to both kainate and quisqualate.
Compared to NMDA receptors, non-NMDA receptors have received less pharmacological scrutiny--the existing antagonists are all competitive--and in vivo research in this area has been hampered by the lack of drugs that cross the blood-brain barrier. Nonetheless, in vivo studies have clearly demonstrated that non-NMDA receptor agonists can be as excitotoxic as NMDA agonists, although longer exposures are required. In addition, evidence from animal studies and from human epidemiological studies suggests that excitotoxicity mediated by non-NMDA receptors may be clinically important in certain pathologies [Ginsberg, M. D., et al. Stroke 20:1627 (1989)].
One such disorder is global cerebral ischemia, as occurs following cardiac arrest, drowning, and carbon monoxide poisoning. Transient, severe interruption of the cerebral blood supply in animal causes a syndrome of selective neuronal necrosis, in which degeneration occurs among special populations of vulnerable neurons (including neocortical layers 3,5 and 6, pyramidal cells in hippocampal zones CA1 and CA3, and small and medium sized striatal neurons). The time course of this degeneration is also regionally variable, and can range from a few hours (striatum) to several days (hippocampus).
NMDA antagonists have generally not proven effective in animal models of global ischemia; indeed, it has been suggested that positive results obtained using NMDA antagonists may largely be artifactual. In contrast, the competitive kainate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline ("NBQX") is dramatically effective in preventing delayed neuronal degeneration following transient forebrain ischemia in both gerbils and rats. Importantly, protection was observed even when NBQX was administered several hours after the ischemic insult. These experiments used relatively large systemic doses of NBQX; evidently this compound crosses the blood-brain barrier only in minute amounts. Thus, there is an urgent need for additional antagonists.
Kainate receptor-mediated excitotoxicity may also play a role in chronic neurological disorders, although the evidence on this point is indirect. It is known that ingestion of some naturally occurring excitatory amino acid agonists can cause symptoms reminiscent of neurodegenerative diseases. These include the cycad plant toxin .beta.-N-methylamino-L-alanine, a possible cause of Guam amyotrophic lateral sclerosis/Parkinsonism-dementia ("ALS/PD"); the chick-pea toxin .beta.-N-oxalylamino-L-alanine, implicated in the etiology of lathyrism; and the mussel toxin domoic acid, whose ingestion causes paralysis and memory impairment. The similarity of these conditions to spontaneously occurring neurodegenerative diseases has led to a proposal that ALS/PD and Alzheimer's disease may involve an excitotoxic component [see Choi, D. W., Neuron 1:623 (1988); and Choi, D. W., Cerebrov. and Brain Metab. Rev. 2:105 (1990)].
It has recently been reported that NMDA antagonists which do not cross the blood/brain barrier may be used to alleviate certain undesirable side effects of cancer chemotherapy, e.g. nausea and emesis [Fink-Jensen, A. et al. Neurosci. Lett. 137(2):173 (1992)]. Because the compounds claimed herein are charged and quite hydrophilic, it may be the case that such compounds have difficulty in crossing the blood/brain barrier. Accordingly, we propose that HF7 discovered by us and its derivatives (see below), being hydrophilic NMDA antagonists with limited blood brain barrier permeability, can be used clinically to ameliorate the side effects of cancer chemotherapy, and chemotherapy in general.
Price, M. T. et al. Soc. Neurosci. Abstr. 16:377, abstr. 161.16 (1990), discloses that the administration of EAA antagonists completely prevented emesis in ferrets that were subject to chemotherapy with cisplatin. The EAA antagonists employed did not penetrate the blood-brain barrier, and it was thus suggested that such compounds may prevent nausea, a common side effect during cancer chemotherapy.
Calcium antagonists such as nimodipine act both as cerebral vasodilators and as calcium channel blockers in neurons [see Wong, M. C. W. et al. Stroke 24:31 (1989) and Scriabine, A., Adv. Neurosurg (1990), respectively]. Modest improvement in the outcome of stroke has been observed in clinical trials [Gelmers, H. J. et al. N. Eng. J. Med. 318:203 (1988)]. While there are significant cardiovascular side effects, nimodipine appears less toxic than the NMDA antagonists and may find a role in the chronic treatment of stroke and other neurological disorders.
There are at least 4 subclasses of calcium channels, "T", "N", "L", and "P", that differ in their pharmacology, location in neuronal and non-neuronal tissues, and physiological properties [Nowycky, M. C. et al. Nature 316:440 (1985); Bean B. P. Ann. Rev. Physiol. 51:367 (1989)]. Voltage-sensitive calcium channels (VSCC) in presynaptic nerve terminals control the influx of Ca.sup.2+ and thereby determine the quantity and duration of transmitter released by the presynaptic action potentials. Biochemical .sup.45 Ca tracer flux experiments with isolated nerve endings (synaptosomes) indicate that K.sup.+ -depolarization dependent .sup.45 Ca entry consists of fast transient and slow sustained components. The transient calcium influx has been determined to represent a channel mediated process, whereas the sustained component reflects calcium entry via reversed Na/Ca exchange [Turner, T. et al. J. Neurosci. 5:841 (1985); Suskziw, J. B. NATO ASI Series, H21:286 (1988); Suszkiw, J. B. et al. J. Neurochem. 42:1260 (1989)].
European Patent Application No. 0 266 574, discloses that calcium overload blockers will be useful in the treatment of anoxia, ischemia, migraine and epilepsy. This application also discloses that certain piperidine derivatives have activity against calcium overload in the brain and may be used in the treatment of migraine.
Dreyer, E. B. et al., Science 248:364 (1990), discloses that the HIV-1 coat protein gp120 produces neuronal cell injury which may be responsible for the dementia and blindness encountered in acquired immunodeficiency syndrome. Calcium channel antagonists prevented the gp120-induced neuronal injury of retinal ganglion cells. Dreyer et al. propose that calcium channel antagonists may prove useful in mitigating HIV-1 related neuronal injury.